# Self-Assembled Rg3/Naringenin Nanoparticles for Targeted Brain Delivery: A Promising Therapeutic Approach for Early Alzheimer’s Disease

## TL;DR

Researchers developed a nanoparticle system to deliver drugs to the brain for early Alzheimer’s disease, improving targeting and safety while reducing harmful brain changes.

## Contribution

A novel self-assembled nanoparticle system (GNN) is introduced for early AD treatment, showing multi-target synergy and a new therapeutic pathway.

## Key findings

- GNN nanoparticles effectively bypass the blood-brain barrier via intranasal delivery and accumulate in brain lesion areas.
- GNN reduces Aβ deposition, oxidative stress, and inflammation in early AD mouse models, improving cognitive function.
- Transcriptomic analysis reveals GNN activates the OXT/ERK/Fos pathway, breaking the ROS–neuroinflammation cycle in early AD.

## Abstract

Background/Objectives: Alzheimer’s disease (AD) has an irreversible disease course, making early intervention a key measure to delay disease progression. However, existing therapies are limited by weak brain-targeted delivery efficiency due to the blood–brain barrier (BBB) and low bioavailability of drugs, making it difficult to address the complexity of AD’s pathological mechanisms. Methods: Addressing these limiting factors, this research aims to develop an early AD intervention formulation with “high targeting, high bioavailability, and high biosafety.” Based on the principle of drug synergistic effects, this study employed the reverse solvent method and optimized the combination ratio of Ginsenoside Rg3 and Naringenin (Nar) to design and prepare a self-assembling nano-delivery system (Rg3-Nar-NPs, GNN). The study utilized intranasal administration to bypass the BBB through the direct pathway between the nasal mucosa and central nervous system. Results: This approach enabled targeted accumulation of the drug in brain lesion areas, significantly reducing Aβ deposition, oxidative stress, and inflammatory factor surges caused by early AD, thereby improving cognitive dysfunction in mice. Moreover, GNN demonstrated superior biosafety and bioavailability compared to the individual components. Through transcriptomic analysis, the study elucidated for the first time that GNN can activate the OXT/ERK/Fos pathway to break the malignant cycle of ROS–neuroinflammation, inhibiting the amplification effect of early AD pathological damage. Conclusions: This research provides new molecular targets and drug options for multi-target synergistic intervention of early AD, showing potential as a candidate strategy for precise early AD intervention and laying theoretical and experimental foundations for subsequent clinical translation.